Impairment in insulin secretion in aging contributes to glucose intolerance and diabetes. We recently showed that humanin (HN), a mitochondria-associated peptide and its potent analog, HNGF6A, improve insulin sensitivity, and lower blood glucose in diabetic rodents. During the course of the studies looking at the effects of HN on insulin action, we identified independent effects of HN on insulin secretion. We demonstrate that HN increases insulin secretion in vivo utilizing hyperglycemic clamp in rodent models, and in vitro using stable beta cell lines in culture and islets isolated from wild type mice and rodent models of diabetes. We demonstrate that treatment with HN is associated with increased plasma membrane localization of GLUT-2 transporters, increased activity of glucokinase enzyme and ultimately, an increase in intracellular ATP leading to an increase in insulin secretion. HN appears to increase insulin secretion through KATP channel independent pathways. In addition, HN decreases oxidative stress and preserves mitochondrial integrity in vitro. Of great clinical relevance are i) the observation that the effects of HN on insulin secretin are glucose sensitive, thus mitigating the risk of hypoglycemia in the elderly and ii) HN augments the effects of GLP-1, an established treatment of diabetes. Based on these preliminary data, and the observation that aging is associated with a decline in HN levels, we hypothesize that administration of HN to aging rodents will substantially improve glucose homeostasis through effects on insulin secretion. In this proposal, using state of the art technology, we will evaluate and characterize the role of HN and HN+GLP-1 on insulin secretion in aging and the molecular mechanisms that mediate this effect. We will study islets isolated from young adult, middle aged and elderly humans to demonstrate the translational potential of HN as a therapeutic option in humans. HN represents a novel molecular link between multiple age related disorders and may provide not only mechanistic explanations but also potential therapeutic options for disorders affecting millions of people.